Chronic Lymphocytic Leukemia Requires BCL2 to Sequester Prodeath BIM, Explaining Sensitivity to BCL2 Antagonist ABT-737

J Clin Invest. 2007 Jan;117(1):112-21. doi: 10.1172/JCI28281.

Abstract

Antiapoptotic B cell leukemia/lymphoma 2 (BCL2) family proteins are expressed in many cancers, but the circumstances under which these proteins are necessary for tumor maintenance are poorly understood. We exploited a novel functional assay that uses BCL2 homology domain 3 (BH3) peptides to predict dependence on antiapoptotic proteins, a strategy we call BH3 profiling. BH3 profiling accurately predicts sensitivity to BCL2 antagonist ABT-737 in primary chronic lymphocytic leukemia (CLL) cells. BH3 profiling also accurately distinguishes myeloid cell leukemia sequence 1 (MCL1) from BCL2 dependence in myeloma cell lines. We show that the special sensitivity of CLL cells to BCL2 antagonism arises from the requirement that BCL2 tonically sequester proapoptotic BIM in CLL. ABT-737 displaced BIM from BCL2's BH3-binding pocket, allowing BIM to activate BAX, induce mitochondrial permeabilization, and rapidly commit the CLL cell to death. Our experiments demonstrate that BCL2 expression alone does not dictate sensitivity to ABT-737. Instead, BCL2 complexed to BIM is the critical target for ABT-737 in CLL. An important implication is that in cancer, BCL2 may not effectively buffer chemotherapy death signals if it is already sequestering proapoptotic BH3-only proteins. Indeed, activator BH3-only occupation of BCL2 may prime cancer cells for death, offering a potential explanation for the marked chemosensitivity of certain cancers that express abundant BCL2, such as CLL and follicular lymphoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis Regulatory Proteins / physiology*
  • BH3 Interacting Domain Death Agonist Protein / drug effects
  • BH3 Interacting Domain Death Agonist Protein / physiology
  • Bcl-2-Like Protein 11
  • Biphenyl Compounds / pharmacology*
  • Cell Death / drug effects*
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Membrane Proteins / physiology*
  • Neoplasm Staging
  • Nitrophenols / pharmacology*
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-bcl-2 / physiology*
  • Sulfonamides / pharmacology*
  • Tumor Cells, Cultured

Substances

  • ABT-737
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • BH3 Interacting Domain Death Agonist Protein
  • Bcl-2-Like Protein 11
  • Biphenyl Compounds
  • Membrane Proteins
  • Nitrophenols
  • Piperazines
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides